Summary for the supplemental request Olfactory dysfunction is often a first symptom of several neurodegenerative diseases, including Alzheimer's disease (AD). Therefore, an improved understanding of how the neural circuitry and functional properties of the olfactory system are altered in models of AD may provide clues to the etiology of AD, as well as potential diagnostic readouts. In the olfactory system, feedback projections from the olfactory cortex to the olfactory bulb may play a critical role in both the detection and analytical processing of odor stimuli. These same projections may be particularly sensitive to AD progression due to their anatomical interface between the olfactory bulb and cortex, two sites of early disease progression. We will test the hypothesis that in a mouse model of AD, disease-related disruption of the morphology and stimulus coding properties of top-down projections to the olfactory bulb impairs olfactory function. In Supplemental Aim 1 we will monitor changes in morphological features of cortical projections to the olfactory bulb through AD-like progression. In Supplemental Aim 2 we will measure the functional properties of feedback projections using naturalistic odor stimuli, combined with in vivo multiphoton imaging and behavioral readouts. These aims are closely aligned with Parent Grant Aim 3, where we will measure the activity of cortical projections to the olfactory bulb to determine how these projections contribute to neural pattern separation and behavioral accuracy on naturalistic odor mixture tasks. The results of our supplemental studies will extend our understanding of the link between AD-like progression and olfactory impairment in two fundamental ways. First, we will gain new insight to the structure and function of long-range projections from the cortex to the olfactory bulb in the context of disease progression. Second, because olfactory dysfunction typically precedes the onset of other disease- related symptoms, we will begin to uncover the breakdown in stimulus coding that may predict a decline in perceptual accuracy that accompanies AD progression. The results we obtain from the completion of this project will provide the basis for future experiments related to plasticity and stimulus discrimination in the context of AD pathology.